The purpose of this study is to determine the course of renal disease in non-insulin-dependent diabetes mellitus (NIDDM) in the Pima Indians and to identify the underlying pathogenetic mechanisms involved in the initiation and progression of renal disease in NIDDM. This project, in part, represents an extension of work previously reported as Project Number Z01 DK 69037. The evolution of micro- to macroalbuminuria and the mechanisms of progressive diabetic glomerular injury (DGI) are being examined. Physiological determinations of glomerular filtration rate (GFR) and its hemodynamic determinants are performed at intervals of 6 months, and they are supplemented with a morphometric analysis of glomeruli in two biopsies separated by an interval of 48 months. The polysucrose Ficoll 70 is also being infused to elucidate the defect in barrier function that underlies proteinuria in early DGI. Mathematical models will be used to compute intrinsic properties of the glomerular capillary walls, including hydraulic permeability, filtration surface area, Kf and the density and distribution of effective radii of functional glomerular pores. By completion of this study we will have serial observations of 6.8 to 8.4 years duration. Principal components analysis and canonical correlations will be used to examine the relationships among continuous variables so as to predict from early findings the anticipated 50 percent of subjects who will advance to overt nephropathy. Because we do not expect the GFR to decline measurably over the observation period, we will also perform an analysis of statistical power on the remaining serial findings, with a view to identifying alternative outcome measures that might be useful in clinical trials. We anticipate that morphological evidence of declining glomerular ultrafiltration capacity may prove to be the most sensitive measure of progression.